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Discover new horizons The goal: achieve the undetectability in all the treated patients Moving from the – Strenght of the drugs – Weakness of the virus – Resources of the host

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Main principles driving the change  Rx based on ethiopatogenetic approach  Long term treatment strategy to save FDO  Avoid long term toxicity  Optimize the drug combination  Put up the goals of cART

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ICAAC 2007, ABS # H-713 Raltegravir Resistance Virologic failure was observed in 38/133 (29%) patients receiving raltegravir in double-blind periodVirologic failure was observed in 38/133 (29%) patients receiving raltegravir in double-blind period –68% of patients with virologic failure had GSS of 0 Genotype data available for all 38 failures:Genotype data available for all 38 failures: –Most patients (35/38) failing raltegravir had integrase mutations conferring raltegravir resistance –Integrase mutations were in either of two genetic pathways (N155 or Q148) in 34 of 35 patients –Resistance was typically associated with two or more mutations (31 of 35 patients) Q148H/G140S was most common (N=13)Q148H/G140S was most common (N=13) *From: Hazuda et al, XVI International HIV Drug Resistance Workshop, 2007, Barbados

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NNRTI RAMS  22 NNRTI * RAMS** identified in the 2007 IAS-USA list  An additional 22 NNRTI RAMs identified in the literature and described by Tambuyzer et al. At the 5° European HIV Drug Resistance Workshop  A final list of 44 NNRTI RAMs at 20 RT*** amino acid positions  37/44 identified associated with an increase in FC to at least one NNRTI when introduced alone in a WT HIV-1/HXB2 backbone by SDM**** (labeled:s)

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57 Why Might CCR5 Inhibition Protect CD4s in the Context of HIV Disease? Maraviroc may block the migration of CCR5+ cells into tissues thereby increasing the number of CD4+ cells in circulation and/or preventing their killing by HIV in tissues Maraviroc may block cellular activation and cytokine expression by preventing signaling through this receptor... ……CD4 recovery only a consequence of antiviral efficacy?